Hypoxia-preconditioned adipose tissue-derived mesenchymal stem cell increase the survival and gene expression of engineered neural stem cells in a spinal cord injury model

Oh, Jin Soo; Ha, Yoon; An, Sung Su; Khan, M. Mumtaz; Pennant, William A.; Kim, Hyo Jin; Yoon, Do Heum; Lee, Minhyung; Kh, Kim

doi:10.1016/j.neulet.2010.02.008

Cited by 70 publications

(44 citation statements)

References 18 publications

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“…Fluorescence-activated cell sorting analysis was performed by annexin-V fluorescein isothiocyanate interaction with phosphatidyl serine. 7 The percentage of annexin-V-positive cells was 30.3±2.1% in untransfected NSCs, 23.7±2.1% in SV-GM-CSF-transfected NSCs and 10.3 ± 0.6% in EpoSV-GM-CSF NSCs. The percentage of annexin-V-positive cells was significantly lower in EpoSV-GM-CSF NSCs, compared with the percentages in other groups.…”

Section: Increased Gm-csf Expression By Nscs Is Activated By In Vitromentioning

confidence: 89%

“…This could then protect transplanted and possible host cells from the hypoxia. 7,8,28,29 Several elements, such as the hypoxia-responsive untranslated region, [30][31][32] oxygen-dependant degradation domain sequence, 33,34 RTP801 promoter 35 and Epo enhancer 31,36 have been used to design hypoxia-inducible systems. We have previously confirmed that the Epo enhancer-based system increases gene expression specifically in hypoxic cells.…”

Section: Discussionmentioning

confidence: 99%

“…The intact, exposed spinal cord was compressed with a vascular clip (width, 2 mm; occlusion pressure, 30 g) for 10 min, as previously described. 7 After removing the clip, transfected NSCs (300 000 cells per 5 ml) were transplanted into the injured or non-injured epicenter of the spinal cord (left of the posterior median sulcus on the T9 level) using a 5-ml Hamilton syringe. All animals received cyclosporine (10 mg kg À1 , Chong Kun Dang Pharm, Seoul, Korea) every day after transplantation.…”

Section: Scimentioning

confidence: 99%

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Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

Kim

et al. 2011

Gene Ther

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the differentiation and function of hematopoietic cells. GM-CSF has been implicated in nervous system function. The goal of the present study was to understand the effects of hypoxia-induced GM-CSF on neural stem cells (NSCs) in a model of spinal cord injury (SCI). GM-CSF-overexpressing NSCs were engineered utilizing a hypoxia-inducible gene expression plasmid, including an Epo enhancer ahead of an SV promoter (EpoSV-GM-CSF). Cells were then subjected to hypoxia (pO 2 , 1%) or a hypoxia-mimicking reagent (CoCl 2 ) in vitro. The progression of time of GM-CSF expression was tracked in EpoSV-GM-CSF-transfected NSCs. Overexpression of GM-CSF in undifferentiated and differentiated NSCs created resistance to H 2 O 2 -induced apoptosis in hypoxia. NSCs transfected with EpoSV-GM-CSF or SV-GM-CSF were transplanted into rats after SCI to assess the effect of GM-CSF on NSC survival and restoration of function. Moreover, a significantly higher amount of surviving NSCs and neuronal differentiation was observed in the EpoSV-GM-CSF-treated group. Significant improvement in locomotor function was also found in this group. Thus, GM-CSF overexpression by the Epo enhancer in hypoxia was beneficial to transplanted NSC survival and to behavioral improvement, pointing toward a possible role for GM-CSF in the treatment of SCI.

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Section: Increased Gm-csf Expression By Nscs Is Activated By In Vitromentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Scimentioning

confidence: 99%

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Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

Kim

et al. 2011

Gene Ther

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“…Previous attempts to determine the migration and persistence of stem cells in vivo include GFP labeling methods and reporter gene analysis [30][31][32][33]. These studies either noted a lack of stem cell persistence, or experienced time-dependent limits of assay efficacy [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

67: Longterm in-Vivo Tumorigenic Assessment of Human Culture-Expanded Adipose Stromal/Stem Cells

Katz

Shang

MacIsaac

et al. 2011

Plastic and Reconstructive Surgery

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After more than a decade of extensive experimentation, the promise of stem cells to revolutionize the field of medicine has negotiated their entry into clinical trial. Adipose tissue specifically holds potential as an attainable and abundant source of stem cells. Currently undergoing investigation are adipose stem cell (ASC) therapies for diabetes and critical limb ischemia, among others. In the enthusiastic pursuit of regenerative therapies, however, questions remain regarding ASC persistence and migration, and, importantly, their safety and potential for neoplasia. To date, assays of in vivo ASC activity have been limited by early end points. We hypothesized that with time, ASCs injected subcutaneously undergo removal by normal tissue turnover and homeostasis, and by the host's immune system. In this study, a high dose of culture expanded ASCs were formulated and implanted as multicellular aggregates into immunocompromised mice, which were maintained for over one year. Animals were monitored for toxicity, and surviving cells quantified at study endpoint. No difference in growth/weight or lifespan was found between cell-treated and vehicle treated animals, and no malignancies were detected in treated animals. Moreover, realtime PCR for a human specific sequence, ERV-3, detected no persistent ASCs. With the advent of clinical application, clarification of currently enigmatic stem cell properties has become imperative. Our study represents the longest duration determination of stem cell activity in vivo, and contributes strong evidence in support of the safety of adipose derived stem cell applications.

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“…Hypoxia preconditioning is a cellular adaptive mechanism elicited by sublethal exposure of cells to low oxygen concentrations (Murry et al, 1986). The stress response that follows will protect cells against subsequent hypoxic insults, leading to improved function and survival through upregulation of antiapoptotic and pro-angiogenic factors in, for example, stem cellbased treatment of myocardial infarction (Azarnoush et al, 2005;Hu et al, 2008), ischaemic disease in limb and brain (Bhang et al, 2011;Rey et al, 2011;Theus et al, 2008) or spinal cord injury (Oh et al, 2010).…”

Section: Modulating Hypoxia Signalling Pathways As a Cellular Protectmentioning

confidence: 99%

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

Stiers

Gastel

Carmeliet

2016

Molecular and Cellular Endocrinology

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a b s t r a c tBone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration.

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Hypoxia-preconditioned adipose tissue-derived mesenchymal stem cell increase the survival and gene expression of engineered neural stem cells in a spinal cord injury model

Cited by 70 publications

References 18 publications

Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury

67: Longterm in-Vivo Tumorigenic Assessment of Human Culture-Expanded Adipose Stromal/Stem Cells

Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration

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